title: PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.
abstract: Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina, United States of America ; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, United States of America.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Barton
authors.forename: Katherine
authors.initials: K
authors.lastname: Misuraca
authors.forename: Francisco
authors.initials: F
authors.lastname: Cordero
authors.forename: Elena
authors.initials: E
authors.lastname: Dobrikova
authors.forename: Hooney D
authors.initials: HD
authors.lastname: Min
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000172:deficiency / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; D016160:Retinoblastoma Protein; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib